201004656 九、發明說明： 【發明所屬之技術領域】 本發明涉及一種液體組成物，特別是涉及一種穩定的 塔三烷類化合物液體組成物及其製備方法和其應用。 【先前技術】 塔三烷類衍生物是可用於藥物領域的雙萜化合物，已 用作卵巢癌、乳腺癌、肺癌等腫瘤的治療劑。以多西他賽 為例（docetaxel/Taxotere)，多西他赛是目前臨床應用效果 ©較好的藥物，也是由法國Rhone-Poulenc Rorer公司開發的 半合成抗腫瘤藥物，在1995年首次上市，可促使微管裝配 (microtubule assembly)，阻止微管分離，抑制腫瘤細胞分 化，最終導致腫瘤細胞死亡，表現出對多種常見腫瘤可靠 的療效，目前已成為臨床應用最廣闊的抗腫瘤藥物。多西 他赛等塔三烷類衍生物一般以濃縮輸注用液體劑型用於臨 床。例如，多西他赛的常規推薦劑量方案是1次/3週，1 ❹小時靜脈輸注75mg/m2。 針對塔三烷類衍生物（例如多西他赛）的靜脈給藥劑型 研究已有很多。此類藥物的水溶性較差，一般將其製成溶 解於表面活性劑和乙醇水溶液的濃溶液，臨床使用時再將 其溶解於輸液中使用。Rowinsky，Lorraine，Cazenave和 Donehower等在1990年8月1日（《國立癌症研究所雜誌》， 82卷，15期：1247-1259)公開了如下配製方法，人們先製 備命名為“母液，，的一種溶液，所述“母液，，為50%體積的乙 醇和50%體積的聚氧伸乙基蓖麻油組成的混合溶液，混合 5 94342 201004656 •溶液中含有約6 mg/ml&紫杉醇，注射時，此溶液用含氯 化鈉或葡萄糖的灌注液混合。 中國專利申請93119653.1和02147245.9中描述了一 種含有塔三院類衍生物的可注射組成物，所述組成物將塔 三烷類化合物多西他赛溶解於吐溫8〇(Tween 8〇)等表面活 !生劑中，再添加乙醇等稀釋劑溶液，所述稀釋劑溶液可盘 表面活性劑溶液分離放置或混合，二者混合後的液體作為 配製臨床輸注使用時的藥物溶液。 ❹美國專利US 5403858A的實施例1具體公開了製備多 西他赛母液的方法，將多西他赛溶解在無水乙醇中，隨後 =入吐溫80，再將乙醇除去，得到母液，母液用州的葡 萄糖灌注液稀釋到濃度為G」、Q 3和q 5mg/mi時觀察所 得稀釋溶液的穩定性。本發明人在此基礎上，對其進行了 研九驚奇地發現，藉由調整母液的生產技術，大大提高 I:?:穩定性，有效成分的降解或有關物質顯著降低， ❹月顯&兩藥物的安全性。 【發明内容】 =發明要解決的技術問題是，提供—種具有較高穩定 別2三炫類衍生物液體組成物。本發明的液體組成物特 ^於製備塔三燒類衍生物的注射劑，如多西他赛的液 =成物或注射製劑（又稱注射劑），且在存放過程中不易 ▼解’更安全有效。 物、容製備多西他賽等塔三貌類的注射劑時，均將藥 ;表面活性劑中，以製得其表面活性劑溶液（又稱 94342 6 201004656 • “母液”），且不須用酸或鹼調節母液的pH值，待母液被稀 釋劑（如葡萄糖溶液或氯化鈉溶液）稀釋後，所得注射液的 pH值適合生理需要。由於該產品本身符合生理需要，因 此，根據一般製劑的製備方法，技術人員不需要也不會調 整其酸鹼性。 θ 本發明的申請人藉由對製劑的各個因素進行考察後， 意外的發現，當在母液的表面活性溶液中添加一定量的酸 性試劑（又稱酸性調節劑），使其成為弱酸性後，母液的穩 ❹定性大大提高。根據US54G3858A的實施例1(下稱原處 工藝）方法，該發明人製得含有表面活性劑的母液，未加入 酸性調節劑調整其酸鹼性時，其pH值為6〇至8〇。而本 發明人經試驗研究發現，若在本品溶液加入酸性調節劑， 將其調整呈弱酸性時，藥液更穩定。採用原處方工藐製備 其母液，在贼條件下，放置10天，測得其有關ς㈣ 含量為11.7%。按照本發明的處方工藝製備其母液，在 〇°C條件下，放置1G天，測得其有關物質的含量為ο·。 由此可見，原處方工藝製得產品的運輸、貯存條件更為苛 刻;而本發明的產品可在常溫條件下長時間放置，有利於 產品的運輸和貯存。上述結果出乎本領域技術人員的預 料。特別是母液pH值為3.0至5〇拉 W時’所得母液不僅提高 了穩疋性’而且被稀釋劑（如葡萄糖溶液或氯化納溶 釋後，所得注射液的ΡΗ值仍然適合生理需要。換而言之， 母液中是否添加酸性調節劑，經稀釋劑稀釋後所得°、、主射 液，均為臨床上可接受的生理pH，如ρΉ4至45左右。 94342 7 201004656 因此，本發明的目的在於提供一種液體組成物，該組 成物為溶解有塔三烷類衍生物的表面活 在於：表面活性劑溶液的pH值在5以下，pH值二 至5，更佳為3.5至4.5。 本文所述的塔三烷類衍生物較佳為下式化合物或其醫 藥上可接受的酯： a201004656 IX. Description of the Invention: [Technical Field] The present invention relates to a liquid composition, and more particularly to a stable liquid composition of a taxane compound, a preparation method thereof and use thereof. [Prior Art] A taxane derivative is a biguanide compound which can be used in the field of medicine and has been used as a therapeutic agent for tumors such as ovarian cancer, breast cancer, and lung cancer. Taking docetaxel as an example (docetaxel/Taxotere), docetaxel is a drug with good clinical application effect. It is also a semi-synthetic anti-tumor drug developed by Rhone-Poulenc Rorer of France. It was first launched in 1995. It can promote microtubule assembly, prevent microtubule separation, inhibit tumor cell differentiation, and ultimately lead to tumor cell death, showing reliable efficacy against many common tumors. It has become the most widely used antitumor drug in clinical application. Taxane derivatives such as docetaxel are generally used in clinical applications in concentrated liquid formulations for infusion. For example, the recommended recommended dosage regimen for docetaxel is 1/3 weeks, with an intravenous infusion of 75 mg/m2 for 1 hour. There have been many studies on intravenous dosage forms for taxane derivatives such as docetaxel. Such drugs are poorly water-soluble, and are generally prepared as a concentrated solution which is dissolved in a surfactant and an aqueous solution of ethanol, and is dissolved in an infusion for clinical use. Rowinsky, Lorraine, Cazenave and Doneyeer et al. published the following formulation method on August 1, 1990 ("National Cancer Institute", Vol. 82, No. 15: 1247-1259), which was first prepared as "mother liquor," A solution, the mother liquor, a mixed solution of 50% by volume of ethanol and 50% by volume of polyoxyethylidene ethyl castor oil, mixed 5 94342 201004656 • The solution contains about 6 mg/ml & paclitaxel, when injected This solution is mixed with a perfusate containing sodium chloride or glucose. An injectable composition containing a derivative of a turf-type compound which dissolves the taxane compound docetaxel on a surface such as Tween 8 〇 is described in Chinese Patent Application Nos. 93119653.1 and 02147245.9. In the living agent, a diluent solution such as ethanol is further added, and the diluent solution can be separated or placed or mixed with a disk surfactant solution, and the mixed liquid is used as a drug solution for preparing a clinical infusion. Example 1 of U.S. Patent No. 5,403,858 A discloses a method for preparing docetaxel mother liquor, which is prepared by dissolving docetaxel in absolute ethanol, followed by Tween 80, and then removing ethanol to obtain a mother liquor. The stability of the resulting diluted solution was observed by diluting the glucose perfusate to concentrations of G", Q3, and q5 mg/mi. On the basis of this, the inventors have made a research and discovery that, by adjusting the production technology of the mother liquor, the I:?: stability, the degradation of the active ingredient or the related substances are significantly reduced, ❹月显& The safety of both drugs. SUMMARY OF THE INVENTION The technical problem to be solved by the invention is to provide a liquid composition having a high stability and a tristimulus derivative. The liquid composition of the present invention is particularly useful for preparing an injection of a tartar derivative, such as a liquid solution or an injection preparation (also known as an injection) of docetaxel, and is not safe and effective during storage. . When preparing injections such as docetaxel and other towers, the drugs are used; in the surfactant, the surfactant solution is prepared (also known as 94342 6 201004656 • “mother liquor”), and does not need to be used. The acid or base adjusts the pH of the mother liquor, and after the mother liquor is diluted by a diluent such as a glucose solution or a sodium chloride solution, the pH of the resulting injection is suitable for physiological needs. Since the product itself meets physiological requirements, the skilled person does not need or adjust its acidity and alkalinity according to the preparation method of the general preparation. θ After reviewing various factors of the preparation, the applicant of the present invention unexpectedly found that when a certain amount of acidic reagent (also called an acid regulator) is added to the surface active solution of the mother liquor to make it weakly acidic, The stability of the mother liquor is greatly improved. According to the method of Example 1 (hereinafter referred to as the original process) of US54G3858A, the inventors prepared a mother liquor containing a surfactant having a pH of 6 Torr to 8 Torr without adding an acid regulator to adjust its acidity and alkalinity. The inventors have found through experiments that if the acid regulator is added to the solution and the acidity is adjusted to be weakly acidic, the solution is more stable. The mother liquor was prepared by the original prescription, and placed under thief conditions for 10 days, and the relevant content of ς(4) was 11.7%. The mother liquor was prepared according to the formulation process of the present invention, and placed at 〇 ° C for 1 G day, and the content of the related substance was measured as ο·. It can be seen that the transportation and storage conditions of the product prepared by the original prescription process are more severe; and the product of the invention can be placed under normal temperature for a long time, which is beneficial to the transportation and storage of the product. The above results are expected by those skilled in the art. In particular, when the pH of the mother liquor is 3.0 to 5 〇W, the obtained mother liquor not only improves the stability and is decomposed by the diluent (such as glucose solution or sodium chloride), the enthalpy of the obtained injection is still suitable for physiological needs. In other words, whether or not the acid regulator is added to the mother liquor, and the pH obtained by dilution with the diluent is the clinically acceptable physiological pH, such as ρΉ4 to 45. 94342 7 201004656 Therefore, the present invention The object is to provide a liquid composition which is a surface in which a taxane derivative is dissolved to have a pH of 5 or less, a pH of 2 to 5, more preferably 3.5 to 4.5. The taxane derivative is preferably a compound of the formula: or a pharmaceutically acceptable ester thereof: a
^中R表示氫原子或乙酿基，Ri表示第三丁氧基_基或 苯甲醯胺基，較佳為多西他赛或其酯。 為了使液體組成物具有所需弱酸性，可在組成物中添 加酸性調節劑，應用於臨床最為合適的組成物可僅由塔三 ❹烷何生物、表面活性劑和酸性調節劑組成，而不含其他物 質，較佳塔三貌類衍生物4多西他賽或其醋。 酸性調節劑可以是本領域常規的調節酸性的有機酸、 ΐ機酸的任—種或其組合。為了方便操作，㈣的酸性調 hi較佳疋♦液狀’4 ’對於固體有機酸或無機酸可將其製 備成σ適☆液使用’較佳為使用乙醇製備酸性調節劑溶 液。所使用的有機酸、無^ ^ 無機酉夂可為本領域常用的酸，例如 ^櫞酸、富馬酸、馬來酸、蘋果酸、鹽酸、硫酸、酒石酸 ’較佳為枸櫞酸’更佳為枸櫞酸的乙醇溶液。酸性調節 94342 8 201004656 劑在組成物中的含量—般為Q Q1至2Qmg/mi，較佳為⑽ 至l〇mg/ml更佳為〇丨至5mg/ml，最佳為〇j至2 ^呂/瓜卜 本發明用於溶解藥物的表面活性劑為本領域常規使用 的表面活性劑’特別是現有技術中用於塔三烧類藥物的表 面活1±齊]如聚氧伸乙基_ (polyoxyethylene ether)、聚氧 =乙基i日（poly〇Xyethylene ester)、甘油醋、氫化萬麻油、 聚氧伸乙基蓖麻油、蓖麻油的任一種或其組合，較佳為聚 氧伸乙基喊’特別是吐溫80。 已有研九發現，塔三烧類化合物的注射用液體，其表 面活性劑溶液中的乙醇含量應儘量地減少，以利於塔三院 _化σ物岭液的穩^性。因此，液體組成物中乙醇的含量 最好不超過1G%，較佳不超過5%，更佳不超過3%，特佳 不超過1.5%。 可根據使用的需要和塔三烷類衍生物在表面活性劑中 的溶解度選擇其在表面活性射的濃度。目前，用於臨床 ❹的注射製劑的濃度一般為每1〇〇ml表面活性劑溶液含玉至 log藥物’多西他赛注射劑的常用濃度為4g/i〇_。 本發明具體提供了一種液體組成物，特別是用於注射 的液體組成物，該組成物由多西他赛、拘拇酸和吐溫⑽ 組成纟中乙醇含1 $ 15%，多西他赛的含量可為 4g/l〇〇nil ° 另-方面’本㈣提供了上述液體組成物在製備治療 腫瘤藥物中的用途。 本發明另-方面提供了一種製備塔三燒類化合物注射 94342 9 201004656 -^ · ., 製割的方法，特別是製備多西妯塞踔鉍制杰， 本發明的注射製d:他赛，射製劑的方法。製備 ，入“主時據常規方法製備得到塔：烷齠π 狄紹^ 劑液，在表面活性劑溶液令添加酸 即劑，調節其邱成為3至5,較佳塔三 生調 他赛或其酯。 凡頰何生物為多西 夕本發明具體提供了一種製備多西他賽注射液 夕西他赛加無水乙醇溶解， 、、， 妁Μ缺a a 丹加入吐，皿80 ’攪拌均勻，用 枸櫞敲之無水乙醇溶液調 用 ❹乙醇含量U.5%。 成為3至5,除去乙醇，至 製備塔三烷類化合物的表 現有技術中公開的方法。2面活^船谷液的方法可採用 量較=溶液’先將塔三炫衍生物溶解於乙 =中4加人表面活性劑，用水性介f稀釋後形成表 1 袠塔三烷衍生物的膠束，藉由真空乾燥法或 ，、他適虽方法除去溶液中的乙醇，至少是部分除去· •„生物直接溶解於表面活性劑中，較佳的方法 疋先製備含有1至2%乙醇的矣而羊从為，、〜 的表活性劑溶液，然後不 斷添加塔三烧衍生物，並使用螺旋㈣機或離 不斷攪拌。 呼微 本文所稱“母液，，是指溶解有塔三烷類化合物的表面活 性劑溶液。測定母液pH值的方法為：取藥液適量，加入 13%(V/V)乙醇溶液’將其稀釋至約1〇mg/mi料三烧類化 合物溶液後，測定其PH值，較佳塔三烧類衍生 他賽或其酯。 94342 10 201004656 除非另有說明 【實施方式】 ’本發明所述百分含量均為重量百分含量 以下將結合實施例具體說明本發明，本發明的實施例 ，用於說明本發日㈣技射案，並非限定本發明的實質。 置施例1 多西他賽母液的製備 多西他賽 20g 吐溫 80 500ml 1公開的方法製備 製備方法：按照US5403858A的實施例 ❹多西他賽母液。 宜·掩例2 多西他赛母液的製備 多西他赛 20g 枸櫞酸乙醇溶液 適量 吐溫 80 500ml 製備方法：稱取多西他赛20g，加無水乙醇1〇〇〇mi，攪拌 溶解’再加人處方量吐溫_8〇(聚山梨料Wherein R represents a hydrogen atom or an ethylenic group, and Ri represents a third butoxy group or a benzamidine group, preferably docetaxel or an ester thereof. In order to make the liquid composition have the desired weak acidity, an acidic regulator may be added to the composition, and the most suitable composition for clinical use may consist of only the trioxane, the surfactant, and the acid regulator, instead of Containing other substances, preferably the tower trimorphic derivative 4 docetaxel or its vinegar. The acidity modifier may be any of the acid-regulating organic acids, oxime acids or combinations thereof conventional in the art. For ease of handling, the acidity of (4) is preferably 疋 ♦ liquid '4 '. For solid organic or inorganic acids, it can be prepared as a sigma ☆ solution. Preferably, an acid regulator solution is prepared using ethanol. The organic acid used, and the inorganic ruthenium, may be an acid commonly used in the art, for example, citric acid, fumaric acid, maleic acid, malic acid, hydrochloric acid, sulfuric acid, tartaric acid, preferably citric acid. A solution of citric acid in ethanol. The content of the acidity adjustment 94342 8 201004656 in the composition is generally Q Q1 to 2Qmg / mi, preferably (10) to l 〇 mg / ml is more preferably 〇丨 to 5 mg / ml, and most preferably 〇 j to 2 ^ Lu/Guab The surfactant used for dissolving the drug in the present invention is a surfactant conventionally used in the art, in particular, the surface activity of the triglyceride in the prior art, such as polyoxyethylene ethyl _ (polyoxyethylene ether), polyoxyl = poly〇Xyethylene ester, glycerin vinegar, hydrogenated cannabis oil, polyoxyethylidene castor oil, castor oil or any combination thereof, preferably polyoxyethylene Base shouting 'especially Twain 80. It has been found in the research and development that the ethanol content of the liquid for injection of the tower tri-sodium compound should be reduced as much as possible to facilitate the stability of the sigma compound. Therefore, the content of ethanol in the liquid composition is preferably not more than 1 G%, preferably not more than 5%, more preferably not more than 3%, and particularly preferably not more than 1.5%. The concentration of the surface active shot can be selected according to the needs of use and the solubility of the taxane derivative in the surfactant. At present, the concentration of the injection preparation for clinical sputum is generally 4 g/i 〇 _ per 〇〇 ml of the surfactant solution containing jade to log drug 'Docetaxel injection. The present invention specifically provides a liquid composition, particularly a liquid composition for injection, which consists of docetaxel, chelating acid and Tween (10). The ethanol contains 1 $15%, docetaxel. The content may be 4 g / l 〇〇 nil ° Another aspect - this (four) provides the use of the above liquid composition in the preparation of drugs for the treatment of tumors. In another aspect of the present invention, there is provided a method for preparing a triazole compound injection 94342 9 201004656 -^, ., a method for making a cut, in particular, a preparation of a doxil sputum, the injection system of the present invention: The method of shooting the preparation. Preparation, into the "mainly according to the conventional method to prepare the tower: alkane π dioxin ^ solution, in the surfactant solution to add acid as an agent, adjust its Qi to become 3 to 5, better tower Sansheng tune or Its ester. Where the buccal organism is the Dorset, the invention specifically provides a preparation of docetaxel injection, oxicillin plus absolute ethanol, and, 妁Μ aa aa dan added to the spit, the dish 80 'stirred evenly, The ethanol content of U. 5% is used to call the ethanol content of U. 5%. It is 3 to 5, and the method of removing the ethanol to the preparation of the taxane compound has the method disclosed in the art. The amount of the solution = solution is first dissolved in the B = H 4 derivative surfactant, diluted with water to form the micelles of the Table 1 decantane derivative, by vacuum drying or , he appropriate method to remove the ethanol in the solution, at least partially removed · • Bio directly dissolved in the surfactant, the preferred method is to prepare the sputum containing 1 to 2% ethanol and the sheep from, The active agent solution, and then continuously add the tower three burning derivative And (iv) using a screw machine or ex constant stirring.呼微 The term "mother liquor" refers to a surfactant solution in which a taxane compound is dissolved. The method for determining the pH of the mother liquor is as follows: take a proper amount of the liquid and add 13% (V/V) ethanol solution to After diluting to about 1 mg/mi of the tri-sodium compound solution, the pH value thereof is determined, and it is preferred to derivatize the derivative or its ester. 94342 10 201004656 Unless otherwise stated [Embodiment] The present invention will be specifically described with reference to the following examples, and the examples of the present invention are intended to illustrate the technical scope of the present invention, and are not intended to limit the essence of the invention. Preparation of the mother liquor Docetaxel 20g Tween 80 500ml 1 Method for preparing preparation Preparation method: Docetaxel mother liquor according to the example of US5403858A. Suitable for masking 2 Preparation of Docetaxel mother liquor Docetaxel 20g枸橼 乙醇 乙醇 乙醇 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80
❹80)，攪拌均勻，用枸櫞酸（用無水乙醇配製）適量調pH 值，經〇.22μιη微孔濾膜過濾，分裝於西林瓶（vial)中，真 空減壓除去乙醇，測定乙醇含量$15%時，加塞並軋外 蓋，即得。 pH值影響多西'他赛製劑穩定性的研究 按照實施例1和2的製備方法’分別製得含有酸性調 節劑（實施例3至9)和不含酸性調節劑（實施例1〇)的母液， 分別於301和2至8。〇放置30天，測定有關考核項目。實 施例10未加枸櫞酸溶液調整母液pH值，其pH值為6 〇 94342 11 201004656 ‘至8.0，結果見表1 : 表1 pH值影響多西他赛製劑穩定性的研究 實施斤 ~~3~ ~~A ~ ~ 7 8 9 10 Ο 枸橼酸用重 (mg/ml) 測定 PH 值 有關 物質 % 含量 % 起始 30°C30 天 2 至 8°C 30天 起始 30°C30 天 2 至 8。。 30天 起始 30°C30 天 2 至 8°C 30天 15 ο ο ο ο 3 3 8 起始 外觀 性狀 30°C30 天 2 至 8°C 30天 520.5.50.1黃黏液黃黏液黃黏液 0.109910淡色辋淡色稠淡色稠 505248535653.8).20.3黃黏液黃黏液黃黏液 33 30·0·0·9910淡色稍淡色钢淡色稍 4.8 3.96 4.00 3.95 0.56 0.55 0.52 101.0 100.4 .9黃黏液黃黏液黃黏液 99淡色稠淡色稠淡色稠 566062526153M0.40.0黃黏液黃黏液黃黏液 4.4.4.0.0.0.91010淡色揭淡色調淡色稱_ 2621225258550.10.5?.7黃黏液黃黏液黃黏液 4.4· 4· 00.0.101099淡色稠淡色稠淡色稠 2 4.88 4.90 4.86 0.54 0.76 0.53 99.8 100.2 100.7 1 5.67 5.66 5.67 0.53 0.83 0.53 100.2 99.7 黃黏液黃黏液黃黏液 淡色稠淡色稠淡色辆 5·黃黏液黃黏液黃黏液 99淡色稠淡色稠淡色拥 ο 6.26 6.20 6.26 0.52 1.22 0.64 100.7 99.4 99.7 黃黏液黃黏液黃黏液 淡色稠淡色稠淡色揭 _ 果表明：當母液的pH值小於5_0時，在30°C條件 下放置一個月，其有關物質的含量明顯小於pH值大於5.0 的母液；pH值為3.5至4.5時，在30Ό條件下放置一個月， 有關物質的含量基本一致。實施例1〇中未加枸櫞酸調節 PH值’測定值為6.26，在30°C條件下放置一個月，其 有關物質明顯高於pH值小於5.0的母液。由此得出，母液 PH值偏弱酸性時，藥液更穩定，尤其當PH值為3.0至5.0 時。 94342 12 201004656 實施例11 本發明液體組成物穩定性的研究 在高温條件下（40°C、60°C、光照45001ux)，放置10 天，進行本發明液體組成物和實施例1穩定性試驗，分別 於0、5、10天取樣，採用高效液相色譜法測定有關物質和 含量，結果見表2、3。 表2 本發明液體組成物的穩定性試驗結果 考核條件 \ 考核 旨標 考核 時間（天）\ 外觀色澤 PH 澄明度 有關物質 (%) 含量 (%) 0 淡黃色黏稠液 3.78 合格 0.52 99.4 40°C 5 淡黃色黏稠液 3.82 合格 0.71 100.3 10 淡黃色黏稠液 3.84 合格 0.84 100.4 0 淡黃色黏稠液 3.78 合格 0.52 99.4 60 °C 5 淡黃色黏辆液 3.83 合格 2.05 98.9 10 淡黃色黏稠液 3.92 合格 3.76 98.1 0 淡黃色黏稠液 3.78 合格 0.52 99.4 45001ux 5 淡黃色黏稠液 3.80 合格 0.58 99.7 10 淡黃色黏稠液 3.81 合格 0.52 99.4 表3 實施例1的穩定性試驗結果 考核 條件 \考核 \旨標 考核\ 時間（天)\ 外觀色澤 pH 澄明度 有關物質 (%) 無菌 檢查 含量(％) 0 淡黃色黏稍液 6.47 合格 1.22 合格 98.4 40°C 5 淡黃色黏稠液 6.44 合格 7.41 合格 91.0 10 淡黃色黏稠液 6.45 合格 11.74 合格 86.6 0 淡黃色黏稠液 6.47 合格 1.22 合格 98.4 60°C 5 黃色黏稠液 6.48 合格 25.97 合格 76.8 10 黃色黏稠液 6.50 合格 26.65 合格 73.3 由此得出，本發明的液體組成物含有酸性調節劑，較 現有技術已知的塔三烷類衍生物母液更為穩定，可在常溫 13 94342 201004656 下長時間放置，利於運輸和貯存。 【圖式簡單說明】 無 【主要元件符號說明】 無❹80), stir evenly, adjust the pH value with citric acid (formed with absolute ethanol), filter through 〇.22μιη microporous membrane, disperse in vial (vial), remove ethanol in vacuum and reduce the ethanol content. At $15%, the plug is rolled and the cover is rolled. The pH value affects the stability of the Dorset's preparations. The preparation methods according to Examples 1 and 2 were prepared to contain an acid regulator (Examples 3 to 9) and an acid-free regulator (Example 1), respectively. Mother liquor, at 301 and 2 to 8, respectively. 〇 Place for 30 days and determine the relevant assessment items. Example 10 The pH of the mother liquor was adjusted without adding a citric acid solution, and the pH value was 6 〇94342 11 201004656 ' to 8.0. The results are shown in Table 1: Table 1 Study on the effect of pH on the stability of docetaxel preparations 3~ ~~A ~ ~ 7 8 9 10 Ο 枸橼 用 用 ( ( ( ( ( ( ( ( ( mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg To 8. . 30 days start 30 ° C 30 days 2 to 8 ° C 30 days 15 ο ο ο ο 3 3 8 initial appearance traits 30 ° C 30 days 2 to 8 ° C 30 days 520.5.50.1 yellow mucus yellow mucus yellow mucus 0.109910 light color 辋Light color thick and light color 505248535653.8).20.3 yellow mucus yellow mucus yellow mucus 33 30·0·0·9910 light color slightly light color steel light color slightly 4.8 3.96 4.00 3.95 0.56 0.55 0.52 101.0 100.4 .9 yellow mucus yellow mucus yellow mucus 99 light color thick and thick Light color thick 566062526153M0.40.0 yellow mucus yellow mucus yellow mucus 4.4.4.0.0.0.91010 light color light color tone light color _ 2621225258550.10.5?.7 yellow mucus yellow mucus yellow mucus 4.4· 4· 00.0.101099 light color thick and light thick and thick 2 4.88 4.90 4.86 4.4 0.54 0.76 0.53 99.8 100.2 100.7 1 5.67 5.66 5.67 0.53 0.83 0.53 100.2 99.7 Yellow mucus yellow mucus yellow mucus light color thick and light color light color 5 · yellow mucus yellow mucus yellow mucus 99 light color thick and light color thick and light ο 6.26 6.20 6.26 0.52 1.22 0.64 100.7 99.4 99.7 Yellow mucus yellow mucus yellow mucus light-colored thick and light-colored thick and light color _ fruit indicates: when the pH of the mother liquor is less than 5_0, placed at 30 ° C for one month, the content of the relevant substances It is less than the mother liquor with a pH greater than 5.0; when the pH is 3.5 to 4.5, it is placed under 30 Ό for one month, and the content of the relevant substances is basically the same. In Example 1, no citric acid was added to the oxime to adjust the pH value to a value of 6.26, which was allowed to stand at 30 ° C for one month, and the related substance was significantly higher than the mother liquor having a pH of less than 5.0. It follows that when the pH of the mother liquor is weakly acidic, the liquid is more stable, especially when the pH is 3.0 to 5.0. 94342 12 201004656 Example 11 Study of the stability of the liquid composition of the present invention Under high temperature conditions (40 ° C, 60 ° C, light 45001 ux), placed for 10 days, the liquid composition of the present invention and the stability test of Example 1, Samples were taken at 0, 5, and 10 days, and the relevant substances and contents were determined by high performance liquid chromatography. The results are shown in Tables 2 and 3. Table 2 Evaluation results of the stability test results of the liquid composition of the present invention\Evaluation time of the evaluation target (days)\ Appearance color PH Clarity related substances (%) Content (%) 0 Light yellow viscous liquid 3.78 Passed 0.52 99.4 40°C 5 light yellow viscous liquid 3.82 qualified 0.71 100.3 10 light yellow viscous liquid 3.84 qualified 0.84 100.4 0 light yellow viscous liquid 3.78 qualified 0.52 99.4 60 °C 5 light yellow sticky liquid 3.83 qualified 2.05 98.9 10 light yellow viscous liquid 3.92 qualified 3.76 98.1 0 Light yellow viscous liquid 3.78 qualified 0.52 99.4 45001ux 5 light yellow viscous liquid 3.80 qualified 0.58 99.7 10 light yellow viscous liquid 3.81 qualified 0.52 99.4 Table 3 Example 1 stability test results Evaluation conditions \ assessment \ target assessment \ time (days) \ Appearance color pH clarity related substances (%) sterility test content (%) 0 light yellow sticky liquid 6.47 qualified 1.22 qualified 98.4 40 ° C 5 light yellow viscous liquid 6.44 qualified 7.41 qualified 91.0 10 light yellow viscous liquid 6.45 qualified 11.74 qualified 86.6 0 light yellow viscous liquid 6.47 qualified 1.22 qualified 98.4 60 ° C 5 yellow viscous liquid 6.48 25.97 Qualified 76.8 10 Yellow viscous liquid 6.50 Qualified 26.65 Qualified 73.3 It follows that the liquid composition of the present invention contains an acidic regulator which is more stable than the tadazine derivative mother liquor known in the prior art, and can be used at a normal temperature of 13 94342. Long-term placement under 201004656 is conducive to transportation and storage. [Simple diagram description] None [Main component symbol description] None
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